Synthesis of 2[(1R,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2, 4-triazol-yl)propyl]-4-[4-tetrafluoropropoxy)phenyl]-3-(2H,4H)-1,2, 4-triazol-3-thioneA Novel and Potent Azole Antifungal Agent

Article abstract of DOI:10.1080/00397910903014232

A simple approach involving refluxing appropriately disubstituted thiosemicarbazide 8 in presence of formic acid for the synthesis of 1, a potent azole antifungal agent, has been described.

Full text of DOI:10.1080/00397910903014232

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Synthesis of 2[(1R,2R)-2-(2,4-
Difluorophenyl)-2-hydroxy-1-methyl-3-
(1H-1,2,4-triazol-yl)propyl]-4-[4-
tetrafluoropropoxy)phenyl]-3-
(2H,4H)-1,2,4-triazol-3-thione—A Novel
and Potent Azole Antifungal Agent
Jitendra A. Sattigeri a , Sachin Sethi a & Mohammad Salman b
a Medicinal Chemistry, New Drug Discovery Research, Ranbaxy
Research Laboratory , Haryana, India
b Ranbaxy Inc. , Princeton, New Jersey, USA
Published online: 22 Feb 2010.
To cite this article: Jitendra A. Sattigeri , Sachin Sethi & Mohammad Salman (2010) Synthesis
of 2[(1R,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-yl)propyl]-4-[4-
tetrafluoropropoxy)phenyl]-3-(2H,4H)-1,2,4-triazol-3-thione—A Novel and Potent Azole Antifungal
Agent, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 40:6, 833-838, DOI: 10.1080/00397910903014232
To link to this article: http://dx.doi.org/10.1080/00397910903014232
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Synthetic Communications1, 40: 833–838, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903014232
SYNTHESIS OF 2[(1R,2R)-2-(2,4-DIFLUOROPHENYL)-
2-HYDROXY-1-METHYL-3-(1H-1,2,4-TRIAZOL-YL)-
PROPYL]-4-[4-TETRAFLUOROPROPOXY)PHENYL]-
3-(2H,4H)-1,2,4-TRIAZOL-3-THIONE—A NOVEL AND
POTENT AZOLE ANTIFUNGAL AGENT
Jitendra A. Sattigeri,1 Sachin Sethi,1 and Mohammad Salman2
1Medicinal Chemistry, New Drug Discovery Research, Ranbaxy Research
Laboratory, Haryana, India
2Ranbaxy Inc., Princeton, New Jersey, USA
A simple approach involving refluxing appropriately disubstituted thiosemicarbazide 8 in
presence of formic acid for the synthesis of 1, a potent azole antifungal agent, has been
described.
Keywords: Azole antifungal; thiosemicarbazide; 1,2,4-triazol-3-thione
BACKGROUND
Incidences of systemic fungal infections have increased significantly over the
past three decades. This has been attributed[1] to a marked increase in the population
of immunocompromised patients with HIV infection or undergoing immunosup-
pressant therapy following organ transplant or chemotherapy. This has led to signifi-
cant morbidity and mortality. As a consequence, there has been a concerted effort by
the pharmaceutical industry and academic laboratories to find safe, potent, and
orally bioavailable antifungal agents.
During the course of our research, we discovered 2-[(1R,2R)-2-(2,4-difluorophenyl)-
2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)
phenyl]-3-(2H,4H)-1,2,4-triazol-3-thione (1) has potent and broad-spectrum activity
against yeast and filamentous fungi.[2] The in vitro activity correlated well with in vivo
protection, indicating adequate pharmacokinetic properties in mice. The initial syn-
thesis of 1 involved Lawesson’s[3a,b] (or modified Lawesson’s[3c]) reagent–mediated
transformation (Scheme 1) of the corresponding triazolone 2[4] to the desired thio
analog.[5] However, we faced several challenges when this transformation was carried
out on a large scale. This reaction did not proceed to completion, and because the
Received January 21, 2009.
Address correspondence to Jitendra A. Sattigeri, Medicinal Chemistry, New Drug Discovery
Research, Ranbaxy Research Laboratory, R&D III, Plot 20, Sector 18, Gurgaon 122 001, Haryana,
India. E-mail: jitendra.sattigeri@ranbaxy.com
833

834
J. A. SATTIGERI, S. SETHI, AND M. SALMAN
Scheme 1. Synthesis of 1 using Lawesson’s reagent.
Rf values of the starting material and the product were similar, column chromato-
graphy often failed to purify the product. Additionally, the Lawesson’s reagent and
its by-product had very foul odors. Therefore, there was a need to develop a robust
and simple synthesis for 1 that would facilitate its generation in multigram quantities.
PRESENT WORK
The construction of the 1,2,4-triazol-3-thione ring system previously reported
involved the cyclization of 2,4-disubstituted thiosemicarbazides in the presence of a
carbon source such as triethylorthoester, formic acid, or formamidine acetate.[6] In
this article, we describe the synthesis of compound 1 based on this protocol. Thus,
in the first step, the epoxy alcohol 3 was converted to the corresponding triflate
derivative with trifluoromethanesulphonic anhydride (Tf2O) in the presence of
Hunig’s base at ꢀ78ꢁC (Scheme 2). The triflate, without any purification, was sub-
jected to nucleophilic substitution with tert-butyl carbazate in dry tetrahydrofuran
(THF) at ꢀ20ꢁC to afford 2-[(1R,2R)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methyl-
propyl-1-tert-butylcarbazate (4) in 61% yield. The epoxy carbazate 4 was treated
with 1,2,4-triazole in the presence of potassium carbonate at 70ꢁC in dry dimethyl-
formamide (DMF) to give the ring-opened product 2-[(1R,2R)-2-(2,4-difluorophe-
nyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-1-tert-butylcarbazate (5) as
a pale yellow solid in 58% yield. Compound 5, on heating with 4-(2,2,3,3-
tetrafluoropropoxy)phenylisothiocyanate (6) in 1,2-dichloroethane at 90ꢁC, gave 1-
tert-butoxycarbonyl-2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,
2,4-triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl] thiosemicarbazide
(7) in 63% yield. Removal of the tert-butoxycarbonyl (BOC) group in compound
7 was accomplished by stirring it with trifluoroacetic acid (TFA) in dichloro-
methane (DCM) at 0ꢁC for 2 h to give Boc-deprotected amine 2-[(1R,2R)-2-(2,
4-difluorophenyl)-2-hydroxy-l-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-4-[4-(2,2,3,3-
tetrafluoropropoxy)phenyl]thiosemicarbazide (8) in 63% yield.
Cyclization of the thiosemicarbazide 8 was the most crucial step in the
synthetic strategy. Initial attempts to cyclize 8 under several conditions, such as
refluxing in the presence of propionic acid=NaOMe in methanol (MeOH) or heating
with formamidine acetate in acetic acid at 80ꢁC, resulted in complex mixtures. How-
ever, when 8 was heated for 2 h in formic acid, the final compound 1 was obtained in
70% yield. Furthermore, as the Boc group is known to be cleaved under strongly
acidic conditions (pH < 1.0; 90ꢁC), we attempted to convert 7 into 1 directly through
an in situ deprotection followed by cyclization in one step. As anticipated, the reac-
tion led to the formation of compound 1, but the yield obtained from 8 was slightly
better than that obtained from 7 (i.e., 70% vs 50%).

SYNTHESIS OF AZOLE ANTIFUNGALS
835
Scheme 2. Formic acid mediated cyclization to 1.
In conclusion, we have developed a new synthetic strategy for the synthesis of
the potent azole antifungal 2 in multigram quantities.
EXPERIMENTAL
Preparation of 2-[(1R,2R)-2-(2,4-Difluorophenyl)-2,3-epoxy-1-
methylpropyl-1-tert-butylcarbazate (4)
(1S)-1-[(2R)-2-(2,4-Difluorophenyl)oxiran-2-yl]ethanol[7] (3) (62.1 g, 0.265 mol),
Hunig’s base (N,N-diisopropylethylamine) (119ml, 0.645 mol), and dichloromethane

836
J. A. SATTIGERI, S. SETHI, AND M. SALMAN
(DCM) (300mL) were placed in a dry, 500-mL, three-neck, round-bottom flask
equipped with a nitrogen inlet, guard tube, addition funnel, and a septum. The mixture
was cooled to ꢀ78ꢁC, and trifluoromethanesulphonic anhydride (55.6 mL, 330.5 mol)
was added dropwise. After the completion of addition, the reaction mixture was stirred
at ꢀ78ꢁC for 30min and at ꢀ20ꢁC for a further 30min. A solution of tert-butyl
carbazate (80.73g, 0.611 mol) in dry tetrahydrofuran (THF) (150mL) was then added.
The reaction mixture was stirred at ꢀ20ꢁC for 2 h followed by stirring at room tempera-
ture for 18h. THF was evaporated in vacuo, and the residue was dissolved in DCM
(150mL). The organic layer was washed with water and brine and dried over sodium
sulfate. The solvent was evaporated in vacuo, and the residue was purified by column
chromatography (silica gel, 100–200 mesh, 6:4 DCM–hexane) to afford the title
1
compound. Yield: 59.6 g (61%). H NMR (300 MHz, CDCI3): d 1.07 (d, J ¼ 6.7 Hz,
3H), 1.46 (s, 9H), 2.79 (d, J ¼ 5 Hz, 1H), 3.08 (d, J ¼ 5 Hz, 1H), 3.22 (q, J ¼ 6.7 Hz,
1H), 5.97 (s, 1H), 6.19 (s, 1H), 6.76–6.90 (m, 2H), 7.35–7.43 (m, 1H). MS m=z (rel.
int.): 337.2 [Mþ 23, 100%].
Preparation of 2-[(1R,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-
3-(1H-1,2,4-triazol-1-yl)propyl]-1-tert-butylcarbazate (5)
Anhydrous K2CO3 (45.3 g, 0.328 mol) was added to a solution of epoxy
carbazate 4 (52.0 g, 0.165 mol) and 1,2,4-triazole (22.6 g, 0.327 mol) in dry DMF
(250 ml) under a nitrogen atmosphere. The reaction mixture was stirred at 40ꢁC
for 15 h and then at 70ꢁC for 4 h. The reaction mixture was poured into ice-cold
water (1000 mL) and extracted with ethyl acetate (EtOAc) (3 ꢂ 200 mL). The
combined organic layers were washed with water and brine and dried over sodium
sulfate. The solvent was removed in vacuo, and the residue was purified by column
chromatography (silica gel, 100–200 mesh, 1:5 EtOAc–DCM) to afford the title
compound. Yield: 37.0 g (58%). 1H NMR (300 MHz, CDC13): d 0. 91 (d, J ¼ 6.7 Hz,
3H), 1.48 (s, 9H), 3.52 (q, J ¼ 6.7 Hz, 1H), 4.75–4.90 (m, 3H), 6.2 (s, 1H), 6.70–6.77
(m, 2H), 7.33–7.41 (m, 1H), 7.73 (s, 1H), 7.90 (s, 1H). MS m=z (rel. int.): 384.0
[MHþ, 70%].
Preparation of 1-tert-Butoxycarbonyl-2-[(1R,2R)-2-(2,4-
difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-
4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]thiosemicarbazide (7)
4-[2,2,3,3-Tetrafluoropropoxy]phenylisothiocyanate 6 (37.92 g, 0.142 mol) was
added to a solution of 5 (36.31 g, 0.095 mol) in 1,2-dichloroethane (170 mL), and
the mixture was heated under reflux for 12 h. The solvent was evaporated, and the
residue was purified by column chromatography (silica gel, 100–200 mesh, 1:10
EtOAc–DCM) to afford the title compound. Yield: 40 g (78%). 1H NMR
(300 MHz, CDC13): d 1.05 (d, J ¼ 6.6 Hz, 3H), 1.51 (s, 9H), 4.35 (t, J ¼ 11.7 Hz,
2H), 4.44 (d, J ¼ 14.5 Hz, 1H), 5.55 (d, J ¼ 14.3 Hz, 1H), 5.82 (s, 1H), 6.07 (tt,
J ¼ 53.1 and 4.9 Hz, 1H), 6.74–6.79 (m, 3H), 6.93–6.96 (d, J ¼ 8. 8 Hz, 2H), 7.36–
7.39 (d, J ¼ 8.8 Hz, 2H), 7.79 (s, 1H), 7.81 (s, 1H), 8.51 (brs, 1H). MS m=z (rel.
int.): 648 [MHþ, 100%].

SYNTHESIS OF AZOLE ANTIFUNGALS
837
Preparation of 2-[(1R,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-l-methyl-
3-(lH-1,2,4-triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)-
phenyl]thiosemicarbazide (8)
A solution of TFA (18 ml.) in dry DCM (60 ml, 30% v=v) was added slowly to a
solution of 1-tert-butoxycarbonyl-2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-
1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]
thiosemicarbazide (7) (3.5 g, 5.4 mmol) in dry DCM (30 ml) at 0ꢁC, and the reaction
mixture was stirred at 0ꢁC for 2 h. The solvents were evaporated in vacuo, and the
residue was dissolved in DCM. The organic layer was washed with 5% aq. NaHCO3
until effervescence ceased. The organic layer was washed with water and brine and
dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the
residue was purified by column chromatography (silica gel, 100–200 mesh, 1:10
EtOAc–DCM) to afford the title compound. Yield: 1.82 g (62.7%), mp 72–76.5ꢁC.
1H NMR (CDC13, 300 MHz): d 1.12 (d, J ¼ 7.0 Hz, 3H), 4.35 (t, J ¼ 11.8 Hz, 2H),
4.48 (d, J ¼ 14.6 Hz, 1H), 4.55 (s, 2H), 5.60 (d, J ¼ 14.6 Hz, 1H), 5.65 (s, 1H), 6.06
(tt, J ¼ 53.1 and 4.9 Hz, 1H), 6.64 (q, J ¼ 6.6 Hz, 1H), 6.73–6.80 (m, 2H), 6.94 (d,
J ¼ 8.9 Hz, 2H), 7.33–7.36 (m, 1H), 7.46 (d, J ¼ 8.9 Hz, 2H), 7.79 (s, 1H), 7.83 (s,
1H), 9.94 (s, 1H). MS m=z (rel. int.): 549.3 [MHþ, 100%].
Preparation of 2-[(1R,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-
3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-
3-(2H,4H)-1,2,4-triazol-3-thione (1)
Method A: From butoxycarbonylthiosemicarbazide 7. A solution of
1-tert-butoxycarbonyl-2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-
1,2,4-triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]thiosemicarbazide
(7) (38 g, 0.2 mol) in formic acid (582 mL) was heated under reflux for 1.5 h, poured
into ice-cold water, and neutralized with 5% aq. NaHCO3. The organic layer was
extracted with EtOAc, washed with water, and dried over sodium sulfate. Solvent
was removed in vacuo, and the residue was purified by column chromatography
(silica gel, 100–200 mesh, 1:1 EtOAc–DCM) to afford the title compound. Yield:
15.31 g (50%), mp: 76.8–84.3ꢁC. 1H NMR (300 MHz, CDCI3):
d 1. 33
(d, J ¼ 6.9 Hz, 3H), 4.34–4.46 (m, 3H), 5.13 (d, J ¼ 14.4 Hz, 1H), 5.21 (s, 1H),
5.88–5.96 (m, 1H), 6.06 (tt, J ¼ 48.5 and 4.6 Hz, 1H), 6.82–6.88 (m, 2H), 7.09–7.12
(m, 2H), 7.53–7.65 (m, 3H), 7.74 (s, 1H), 7.93 (s, 1H); MS m=z (rel. int.): 559
[MHþ, 100%].
Method B: From thiosemicarbazide 8. A solution of 2-[(1R,2R)-2-(2,4-
difluorophenyl)-2-hydroxy-l-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-4-[4-(2,2,3,3-
tetrafluoropropoxy)phenyl]thiosemicarbazide (8) (1.5 g, 2.73 mmol) in formic acid
(3.0 ml) was heated under reflux for 2 h, poured in ice-cold water, and neutralized
with 5% aq. NaHCO3. The organic layer was extracted with EtOAc, washed with
water, and dried over NaSO4. Solvent was removed in vacuo, and the residue was
purified by column chromatography (silica gel, 100–200 mesh, 1:1 EtOAc–DCM)
to afford the title compound. Yield: 1.021 g (70%).

838
J. A. SATTIGERI, S. SETHI, AND M. SALMAN
ACKNOWLEDGMENT
The authors thank Dr. Ian Cliffe for reading the manuscript and recommending
necessary changes.
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